HIV-1 is a global epidemic spread predominantly through sexual contact and through the use of injectable drugs, such as heroin. Since the implementation of cART (Combined Active Antiretroviral Therapy) in the mid 1990's, infected individuals are living longer with HIV-1 and AIDS, which augments the neurological and psychological profiles associated with HIV-1. Collectively, these CNS deficits are known as HIV-1 associated neurocognitive disorders (HAND) and include HIV-associated dementia (HAD) and HIV-associated encephalitis (HIVE). Broadly, HAND syndromes are characterized by cognitive, motor and behavior dysfunctions; indicative of basal ganglia dysfunction [7,34,42,75]. In conjunction with high viral load in patients, the striatal region within the basal ganglia preferentially has a high abundance of mu- opioid receptor (MOR) expression [24]. Opioids are known to modulate immune function and this confound is likely to worsen the pathogenesis and neurological complications of HIV-1 [20,44-6,66,74]. The viral coat glycoprotein of HIV-1, gp120, is an established neurotoxin that is required for viral entry and infection, and its extracellular actions are toxic to neurons and glia (microglia and astrocytes) in vitro and in vivo in both human and rodent models [4,5,9,11,12,15,17,19,35,50,51, 60,61,70]. Our lab and others have demonstrated how opioids potentiate this gp120 induced neurotoxicity [1,28,45]. We have shown that gp120 increases caspase-3 activity and induces apoptosis of striatal neurons. We are interested in better understanding how opioids affect HIV-gp120 induced neurotoxicity within the striatum and specifically want to investigate the role of caspase-3 in both glial and neuronal mediated mechanisms of neurotoxicity. Studies are proposed to determine if glial caspase-3 mediates gp120 neurotoxicity 1 opioids, and to establish whether opioids act via caspase-3 to directly affect neuron injury and/or death in vitro using caspase-3 knockout cells. Finally, we wil employ the use of caspase-3 knockout mice to investigate how genome-wide deletion of the executioner caspase will affect glial and neuronal responses after gp120 1 opioids in vivo. Collectively, the proposed studies will add to the understanding of how caspase-3 plays a role in the interactive co-morbidity of gp120 and opioids in regards to HIV neuropathogenesis. With this information, a better understanding of underlying mechanisms are made possible which lead to new options in therapeutics, which have ramifications for opioid abusers and users infected with HIV-1. PUBLIC HEALTH RELEVANCE: HIV-positive opioid drug abusers show an expedited progression to AIDS and since infected individuals are living longer with current antiretroviral therapy there is an increasing rate of HIV-associated neurocognitive disorders including dementia. Our research will help identify potential therapeutic agents for the prevention and treatment of neurocognitive dysfunction in HIV-positive individuals using and/or abusing opioids.